Analgesic/antiinflammatory patches for topical use

ABSTRACT

The invention provides an analgesic anti-inflammatory patch of a hydrophobic type for topical application containing, in a Pressure Sensitive Adhesive (PSA), diclofenac sodium, pyrrolidone or a derivative thereof, a polyhydric alcohol fatty acid ester, and an organic acid. The patch exerts the following effects:  
     (1) diclofenac sodium is effectively and continuously released from a Pressure Sensitive Adhesive (PSA) and percutaneously absorbed, thereby attaining sustained, excellent pharmaceutical and pharmacological effects;  
     (2) the patch per se has high tackiness and safety; and  
     (3) diclofenac sodium remains stable in the Pressure Sensitive Adhesive (PSA).

TECHNICAL FIELD

[0001] The present invention relates to a patch containing diclofenacsodium as an active ingredient, the patch exhibiting excellentreleasability and percutaneous absorbability of diclofenac sodium andexerting a stable analgesic anti-inflammatory effect for a long periodof time upon topical application.

BACKGROUND ART

[0002] Diclofenac sodium exerts excellent antipyretic, analgesic, andanti-inflammatory effects. Drug preparations containing diclofenacsodium are generally divided into peroral drugs exhibiting a systemicaction and drugs for external use exhibiting a topical action. When aperoral drug is administered, grave, systemic adverse effects such asgastrointestinal disorders occur, thereby calling for furtherdevelopment of percutaneous-absorption-type patches for topicalapplication for mitigating such adverse effects. In connection with apatch containing a non-steroidal analgesic anti-inflammatory drug suchas diclofenac sodium, the most important issues are effective, sustainedpercutaneous absorption of the active ingredient into the disturbedportion directly under the patch and delivery of the active ingredientto the disturbed portion directly under the patch.

[0003] Since diclofenac sodium has considerably low solubility in waterand an oily component, a wide range of studies have been carried out inorder to stabilize it in a dissolved state in a drug for external usefor promoting percutaneous absorption from a patch. For example,Japanese Patent Application Laid-Open (kokai) No. 61-280426 disclosesincorporation of an organic acid (citric acid) as an additive forenhancing the solubility and percutaneous absorbability of diclofenacsodium. Japanese Patent Application Laid-Open (kokai) No. 4-193826discloses incorporation of an essential oil component such as menthol ormentha oil as a percutaneous absorption promoter for diclofenac sodium.Japanese Patent Application Laid-Open (kokai) No. 5-178763 disclosesincorporation of a polyhydric alcohol medium-chain fatty acid ester as asolubilizer for slightly soluble drugs. Japanese Patent ApplicationLaid-Open (kokai) No. 11-222443 discloses incorporation of 1-menthol anda pyrrolidone (pyrrolidone or at least one derivative thereof) as apercutaneous absorption promoter for diclofenac sodium.

[0004] However, percutaneous absorbability of a drug containingdiclofenac sodium for external use is still unsatisfactory, and thus,there still remains a need for a drug for external use which promisesmore effective percutaneous absorption.

[0005] Thus, an object of the present invention is to provide a patchwhich exhibits excellent releasability and percutaneous absorbability ofdiclofenac sodium.

DISCLOSURE OF THE INVENTION

[0006] The present inventors have carried out extensive studies in orderto solve the aforementioned problems, and have found that, byincorporating pyrrolidone or a derivative thereof, a polyhydric alcoholfatty acid ester, and an organic acid in combination into a PressureSensitive Adhesive (PSA) containing diclofenac sodium, there can beproduced a patch of a hydrophobic type which attains a consistentlydissolved state of diclofenac sodium in the PSA; exhibits excellentreleasability of diclofenac sodium from the PSA and excellentpercutaneous absorbability of diclofenac sodium; and exerts a stableanalgesic anti-inflammatory effect for a long period of time.

[0007] Accordingly, the present invention provides an analgesicanti-inflammatory patch of a hydrophobic type for topical applicationcontaining, in a PSA, diclofenac sodium, pyrrolidone or a derivativethereof, a polyhydric alcohol fatty acid ester, and an organic acid.

BRIEF DESCRIPTION OF THE DRAWINGS

[0008]FIG. 1 is a graph showing dissolution of diclofenac sodiumcontained in tested patches.

[0009]FIG. 2 is a graph showing transdermal permeability of diclofenacsodium released from tested patches.

BEST MODES FOR CARRYING OUT THE INVENTION

[0010] The patch of the present invention contains, in a PSA, diclofenacsodium, pyrrolidone or a derivative thereof, a polyhydric alcohol fattyacid ester, and an organic acid. As mentioned above, diclofenac sodiumis an active ingredient of the patch of the present invention.Preferably, diclofenac sodium is incorporated, as an active ingredient,into a PSA layer in an amount of 0.1-5.0 wt. %, more preferably 0.5-4.0wt. %. From another viewpoint, diclofenac sodium is preferablyincorporated into a PSA layer in an amount, per skin-contact area, of5-2,000 μg/cm², more preferably 50-400 μg/cm². In the context of thepresent invention, the “PSA layer” does not include the support; i.e.,the “PSA layer” refers to a layer containing the aforementionedingredients and other ingredients in the PSA.

[0011] Examples of the above pyrrolidone or derivative thereof include2-pyrrolidone and N-alkyl-2-pyrrolidones, with 2-pyrrolidone andN-methyl-2-pyrrolidone being particularly preferred. These pyrrolidoneand derivetives thereof function as a solubilizer for diclofenac sodium,and each pyrrolidone species is preferably incorporated into a PSA layerin an amount of 0.5-8.0 wt. %, more preferably 1.0-5.0 wt. %.

[0012] Examples of the polyhydric alcohol fatty acid ester includealcohol (dihydric to tetrahydric) fatty acid esters; e.g., glycerinfatty acid esters, ethylene glycol fatty acid esters, propylene glycolfatty acid esters, sorbitan fatty acid esters, and pentaerythritol fattyacid esters. Specific examples include glycerin mono-(C6-C18) fatty acidesters, ethylene glycol mono-(C6-C18) fatty acid esters, propyleneglycol mono-(C6-C18) fatty acid esters, sorbitan mono-(C6-C18) fattyacid esters, propylene glycol di-(C6-C18) fatty acid esters, andpentaerythritol tetra-(C6-C18) fatty acid esters. Of these, glycerinfatty acid esters (e.g., glyceryl tri(caprylate.caprate)), ethyleneglycol fatty acid esters, pentaerythritol fatty acid ester (e.g.,pentaerythrityl tetra-2-ethylhexanoate), and propylene glycol fatty acidesters (e.g., propylene glycol monocaprylate and propylene glycoldicaprylate) are more preferred. Of these, propylene glycol fatty acidesters are still more preferred. Examples of commercial products ofthese esters include Sefsol (product of Nikko Chemicals Co., Ltd.).These polyhydric alcohol fatty acid esters function as a percutaneousabsorption promoter for diclofenac sodium and may be used in combinationof two or more species. The ester is preferably incorporated into a PSAlayer in an amount of 0.2-10.0 wt. %, more preferably 0.5-5.0 wt. %.

[0013] Examples of the organic acid include C3-C6 dicarboxylic acids andC3-C6 tricarboxylic acids. Of these, citric acid, tartaric acid, andsuccinic acid are preferred. These organic acids function aspercutaneous absorption promoters for diclofenac sodium and may be usedin combination of two or more species. The organic acid is preferablyincorporated into a PSA layer in an amount of 0.05-4.0 wt. %, morepreferably 0.1-2.0 wt. %.

[0014] As mentioned above, both the polyhydric alcohol fatty acid esterand the organic acid function as percutaneous absorption promoters fordiclofenac sodium. The ratio by weight of the polyhydric alcohol fattyacid ester to the organic acid preferably falls within a range of 1:20to 200:1, more preferably 1:4 to 50:1. The total amount of thepolyhydric alcohol fatty acid ester and the organic acid incorporatedinto a PSA layer preferably falls within a range of 0.25-14 wt. %, morepreferably 0.6-7 wt. %.

[0015] The PSA into which the above components are to be incorporated isformed from a PSA base and a tackifier in combination. A preferable PSAbase is a styrene-isoprene-styrene block copolymer (SIS). The SIS iscommercially available, and examples of commercial products includeCariflex TR-1107 and Cariflex TR-1117 (trade names; product of ShellKagaku K.K.). The amount of the PSA base incorporated into a PSA layerpreferably falls within a range of 10-50 wt. %, more preferably 10-40wt. %.

[0016] Examples of the tackifier include rosin ester resin, polyterpeneresin, terpene phenol resin, and petroleum resin. Of these, rosin esterresin is preferred, with a rosin ester resin which has been subjected toremoval of low-boiling fractions and subsequent hydrogenation (e.g.,Ester Gum HG, product of Arakawa Chemical Industries, Ltd.) beingparticularly preferred. YS Resin (polyterpene resin, product of YasuharaYushi Kogyo Co., Ltd.), YS Polyster (terpene phenol resin, product ofYasuhara Yushi Kogyo Co., Ltd.), Quintone (petroleum resin, product ofNippon Zeon Co., Ltd.), Arkon (petroleum resin, product of ArakawaChemical Industries, Ltd.), Escorez (petroleum resin, product of ExxonCorp.), and other similar products may be used. The amount of thetackifier incorporated into a PSA layer preferably falls within a rangeof 5-50 wt. %, more preferably 5-30 wt. %.

[0017] The patch of the present invention may further contain arbitrarycomponents such as an essential oil component (e.g., 1-menthol or menthaoil); a softening agent (e.g., liquid paraffin); an antiageing agent; ora filler (inorganic compound). In addition to diclofenac sodium, thepatch of the present invention may further contain another drugcomponent such as ketoprofen, indomethacin, flurbiprofen, glycolylsalicylate, methyl salicylate, capsaicine, nonyl vanillylamide,tocopheryl acetate, a phellodendron bark extract, or an AesculusHippocastanum Seed extract. The softening agent is preferablyincorporated into a PSA layer in an amount of 30-70 wt. %, morepreferably 40-60 wt. %. The essential oil component is preferablyincorporated into a PSA layer in an amount of 0.2-5.0 wt. %, morepreferably 0.5-3.0 wt. %.

[0018] As mentioned above, the PSA layer included in the patch of thepresent invention is of hydrophobic type and contains substantially nowater. This feature renders the present invention fundamentallydifferent from that of conventional cataplasms.

[0019] The patch of the present invention can be produced by spreadingthe aforementioned PSA base on a soft support. Any type of support canbe employed so long as the support is formed of a soft sheet which doesnot permit permeation of the PSA base through the back of the support.Examples of the sheet employable as the support of the present inventioninclude woven and non-woven fabrics; plastic films such as polyolefinfilm, polyvinyl alcohol film, vinyl chloride film, urethane alloy film,urethane-vinyl chloride copolymer film, and ethylene-vinyl acetate film;film of a foamed blend of acrylic polymer or polystyrene-polybutadieneand polyisoprene; these films on which metal is coated through vapordeposition; and laminated sheets obtained from two or more species ofthese films. Appropriately, the support typically has a thickness ofabout 1,000 μm or less, preferably 30-700 μm.

[0020] The thus-produced patch of the present invention is applied toskin sites where an analgesic anti-inflammatory effect is needed; e.g.,inflammation sites of the joints, muscles, neck, etc.

EXAMPLES

[0021] The present invention will next be described in more detail byway of examples, which should not be construed as limiting the inventionthereto.

Examples 1 to 4

[0022] In each example, a PSA base and a softening agent shown in Table1 were kneaded by use of a heating-kneader. A tackifier was added to thekneaded product, and the resultant mixture was further kneaded.Subsequently, diclofenac sodium was dissolved in a liquid mixturecontaining pyrrolidone, a polyhydric alcohol fatty acid ester, andcitric acid, and the resultant solution was added to the above kneadedproduct. The resultant mixture was further kneaded, to thereby yield auniform mixture. The mixture was applied to and spread on a support, tothereby form a PSA layer. After an appropriate period of time, the PSAlayer was covered with a liner, and the resultant laminated product wascut into pieces of desired dimensions, to thereby obtain patches. TABLE1 (wt. %) Ex. 1 Ex. 2 Ex. 3 Ex. 4 PSA base SIS 28.5 28.5 38.0 30.0Polyisobutylene  2.0 — —  4.0 Tackifier Ester Gum HG*¹ 12.0 12.0 20.025.0 Softening agent Liquid paraffin 50.1 50.1 33.8 32.7 Solubilizer2-Pyrrolidone  4.0  4.0  2.0  1.0 Absorption promoter Sefsol*²  2.0  2.0 4.0  3.0 Citric acid  0.4  0.4  0.2  0.3 Tackiness regulator 1-Menthol 2.0  1.0  3.0 Drug ingredient Diclofenac sodium  1.0  1.0  1.0  1.0

Test Example 1 (Dissolution Test)

[0023] The time-elapsed dissolution amount of diclofenac sodium releasedfrom each patch was determined through a paddle over disk method by useof a dissolution tester according to Japanese Pharmacopoeia.Specifically, each test patch was cut into pieces (5 cm×5 cm), and eachpiece was bonded to Teflon mesh. The piece was clamped by two pieces ofwatch glass and placed in a phosphate buffer (900 mL, pH: 7.2) at 32° C.A paddle was rotated 25 mm above the patch, and a liquid (1 mL) wassampled at an intermediate level between the bottom of the paddle andthe liquid surface. The sampling was performed 0.5, 1, 2, 3, 4, 6, and 8hours after paddle rotation. Diclofenac sodium contained in each sampledliquid was quantitated through high performance liquid chromatography.

[0024] The patches prepared in the above Examples 1 to 4 and thoseprepared in Comparative Examples were employed as test patches. Testpatches of Comparative Examples were prepared in accordance with theformulations shown in Table 2 in a manner similar to those employed inExamples 1 to 4. TABLE 2 (wt.%) Comp. Comp. Comp. Comp. Comp. Comp. Ex.1 Ex. 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 SIS 28.5 28.5 28.5 28.5 28.5 28.5Polyiso-  2.0  2.0  2.0  2.0 — — butylene Ester Gum HG 12.0 12.0 12.012.0 12.0 12.0 Liquid paraffin 54.0 50.0 54.5 56.1 58.5 52.5 Pyrrolidone—  4.0 — — —  4.0 Sefsol — —  2.0 — —  2.0 Citric acid — — —  0.4 — —1-Menthol  2.5  2.5 — — — — Diclofenac Na  1.0  1.0  1.0  1.0  1.0  1.0

[0025] Each of the thus-determined diclofenac sodium levels wasconverted to the corresponding percent dissolution from the patch (%).The results are shown in FIG. 1. In FIG. 1, “Mean,” “SD,” and “n” denotea mean value, a standard deviation, and the number of test samples,respectively.

[0026] The results indicate that the patches according to the presentinvention exhibit percent dissolution as high as four times or more thatof all patches of Comparative Examples 1 to 6.

Test Example 2 (Transdermal Permeability Test)

[0027] Hairless rats (body weight: 170 g) were anesthetized bypentobarbital. After removal of hair from the abdomen, abdominal skinsamples were extirpated. Each of the thus-extirpated skin samples wasset in a vertical cell (effective permeation area: 2.83 cm², cellcapacity: 16 mL), and a test patch (diameter: 1.9 cm) was attached tothe skin sample. Subsequently, the receiver liquid in the cell wasstirred by means of an electromagnetic stirrer while the cell was heatedat 37° C. A portion (0.5 mL) of the receiver liquid was sampled aplurality of times at constant time intervals, and the diclofenac sodiumcontent of the liquid portion was determined.

[0028]FIG. 2 shows cumulative permeation amounts of diclofenac sodiumthat had been released from each patch sample and had permeated eachextirpated skin sample of the abdomen of each rat (Examples 1 and 2 andComparative Examples 1 to 6). As is clear from FIG. 2, the patchesaccording to the present invention exhibit cumulative permeation amountsas high as about three times or more those of patches of ComparativeExamples 1 to 6.

[0029] The results of Test Examples 1 and 2 indicate that the patch ofthe present invention can exhibit remarkably promoted releasability andpercutaneous absorbability of diclofenac sodium which conventionaltechniques have not satisfactorily attained. Thus, the patch of thepresent invention has proven to be a clinically useful patch whichmitigates systemic adverse effect and provides other advantages.

INDUSTRIAL APPLICABILITY

[0030] The patch of the present invention exerts the following effects:

[0031] (1) diclofenac sodium is effectively and continuously releasedfrom a PSA and percutaneously absorbed, thereby attaining sustained,excellent pharmaceutical and pharmacological effects;

[0032] (2) the patch per se has high tackiness and safety; and

[0033] (3) diclofenac sodium remains stable in the PSA.

1. An analgesic anti-inflammatory patch of a hydrophobic type fortopical application containing, in a Pressure Sensitive Adhesive (PSA),diclofenac sodium, pyrrolidone or a derivative thereof, a polyhydricalcohol fatty acid ester, and an organic acid.
 2. A patch as describedin claim 1, wherein the pyrrolidone or the derivative thereof is2-pyrrolidone or N-methyl-2-pyrrolidone and the organic acid is citricacid, tartaric acid, or succinic acid.
 3. A patch as described in claim1 or 2, wherein the Pressure Sensitive Adhesive (PSA) contains astyrene-isoprene-styrene block copolymer and a tackifier.
 4. A patch asdescribed in any one of claims 1 to 3, which contains, in a PressureSensitive Adhesive (PSA) layer, diclofenac sodium in an amount of0.1-5.0 wt. %, pyrrolidone or a derivative thereof in an amount of0.5-8.0 wt. %, a polyhydric alcohol fatty acid ester in an amount of0.2-10.0 wt. %, and an organic acid in an amount of 0.05-4.0 wt. %.
 5. Apatch as described in any one of claims 1 to 4, wherein the PressureSensitive Adhesive (PSA) contains, in a Pressure Sensitive Adhesive(PSA) layer, a styrene-isoprene-styrene block copolymer in an amount of10-50 wt. % and a tackifier in an amount of 5-50 wt. %.